Iron Overload Pattern in Multiple Myeloma at Diagnosis its Important

ULUSLARARASI HEMATOLOJI-ONKOLOJI DERGISI
ARTICLE
International Journal of Hematology and Oncology
Iron Overload Pattern in Multiple Myeloma
at Diagnosis its Important Clinical Associations
Eylem ELIACIK1, Berfu KORUCU2, Seda BALABAN2, Ayse ISIK1, Ibrahim C. HAZNEDAROGLU1,
Hakan GOKER1, Salih AKSU1, Nilgun SAYINALP1, Yahya BUYUKASIK1
Hacettepe University, Faculty of Medicine, Department of Hematology
Hacettepe University, Faculty of Medicine, Department of Internal Medicine, Ankara, TURKEY
1
2
ABSTRACT
As a plasmaproliferative disorder, multiple myeloma (MM) is not expected to cause IO and actually there are no reports on this condition in
MM. In this retrospective study, we evaluated serum iron test results in MM patients at diagnosis in order to find the frequency of IO. Iron
overload pattern (IOP) was described as increased transferring saturation (> 45%) in the presence of normal to increased serum iron and
ferritin levels. Among 90 newly diagnosed MM patients (54 male, 36 female, and the median age: 61 years, range: 31-86) IOP was found
in 17 cases (17/90, 19%). There was a close association between lambda light chain type paraproteinemia and IOP (13/17 in IOP cohort
vs 26/73 lambda paraproteinemia, p= 0.003). Half of the MM patients (7/14) with free lambda light chain paraproteinemia had IOP. The
main reason of the elevated TS was increased serum iron level in IOP patients, 144 (±71) vs 57 (±24) pg/ml (p< .001). Four out of 17 IOP
patients had extramedullary involvement and this was significantly more frequent than the other patients. Although high International Staging System risk disease (stage 2 or 3) was more frequent in IOP patients (15/15 vs 51/68, p= 0.03), we could not observe any difference
regarding treatment response, and survival between these cases and others. In conclusion, IO is also not infrequent MM at diagnosis and
it has some clinical associations.
Keywords: Multiple myeloma, Iron overload
ÖZET
Myelom Hastalarında Tanı Anında Demir Yüklenme Sıklığı ve Bunun Klinik Önemi
Plazma proliferatif bir hastalık olan multiple myelomun demir yüklenmesine neden olması beklenmediği gibi bu durumla ilgili herhangi bir
bilgi bulunmamaktadır. Bu retrospektif çalışmada, multiple myelom hastalarını demir yüklenme sıklığını öğrenmek için tanı anındaki serum
demir testleri ile incelendi. Demir yüklenme paterni, normal- yüksek serum demir ve ferritin düzeyi varlığında, transferin saturasyonunun
>%45 olması olarak kabul edildi. Yeni tanı almış 90 MM hastasından (54 erkek, 36 kadın ve ortalama yaş 61, yaş aralığı 31-86 yıl) 17’sinde
(17/90,%19 )demir yüklenme paterni saptandı. Lambda hafif zincir tip paraproteinemi ile demir yüklenmesi arasında yakın ilişki vardı (13/17
demir yüklenme paterni ve 26/73 lambda proteinemi, p= 0.003) .Serbest lambda hafif zincir tip MM hastalarının yarısında (7/14) demir
yüklenme paterni vardı. Artmış transferin saturasyonu azalmiş total demir bağlama kapasitesinden kaynaklanmıyordu. Total demir bağlama
kapasitesi değeri, demir yüklenmesi olan ve olmayan gruplarda benzerdi. Artmış TS’ unun asıl nedeni serum demir değerinin artmasıydı
144 (±71) vs 57 (±24) pg/ml (p< 0.001). Demir yüklenmesi olan 17 hastanın 4’ ünde ekstramedüller tutulum vardı ve bu oran diğer hastalardan anlamlı olarak daha fazlaydı. Yüksek ISS(stage 2 ya da 3) skoruna sahip hastalar demir yüklenmesi olan grupta daha sık olmakla
birlikte (15/15 vs 51/68, p= 0.03) , bu grup ile diğerleri arasında tedavi yanıtı ve yaşam süreleri açısından herhangi bir fark gözlemlenmedi .
Özetle; demir yüklenmesi yeni tanı MM hastalarında sıkça görülür ve bazı klinik sonuçları vardır.
Anahtar Kelimeler: Multiple myelom, Demir yüklenmesi
UHOD Number: 3 Volume: 24 Year: 2014
doi: 10.4999/uhod.14229
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International Journal of Hematology and Oncology
INTRODUCTION
Multiple myeloma (MM) is a chronic incurable malignant plasma cell disease. The systemic and/or localized collection of the neoplastic plasma cells may
complicate the clinical course of MM with or without
bone marrow involvement.1-3 The serum ferritin was
suggested to be a prognostic parameter of survival as
well as disease activity in patients with MM.4 The potential role of the iron in bortezomib-resistance has
also been suggested.5 Likewise, targeting the human
transferrin receptor 1 (CD71) may be effective in the
potential experimental therapy in human MM.6 Iron
overload (IO) may occur in hematologic neoplastic
disorders that are associated with ineffective hematopoiesis, such as myelodysplastic syndrome and acute
myeloid leukemia. As a plasmaproliferative disorder,
MM is not expected to cause IO and actually there are
no reports on this condition in MM.
The aim of this study is to assess frequency and clinicopathological associations of IO in MM patients at
diagnosis. Iron may have a place in the pathobiology
of MM6-11 and its management.5,6,11 Elucidation of IO
in MM may help better understanding the pathobiology of the disease and even better management of the
patients.
PATIENTS AND METHODS
All MM patients who had been followed in Hacettepe
University Faculty of Medicine Department of Hematology during last 10 years have been reviewed
in order to find cases with available serum iron test,
i.e., serum iron, total iron binding capacity (TIBC)
and ferritin levels, at diagnosis. Patients with known
chronic liver disease, chronic inflammatory disorder
or infection within one month of serum iron testing
were not included in the study. Transferrin saturation
(TS) was calculated by dividing serum iron level to
TIBC. Iron overload pattern (IOP) was described as
increased TS (> 45%) in the presence of normal to
increased serum iron and ferritin levels 12. In case
of decreased TS and ferritin levels and normal to increased TIBC pure iron deficiency (PID) was diagnosed. If serum iron and TIBC levels were decreased
and ferritin was normal to increased pure inflammation anemia (PIA) was considered. When TS was decreased but the other tests were not compatible with
PID or PIA, the diagnosis was indiscernible between
iron deficiency and inflammation (IIDI). Other deviated serum iron test results were considered nonspecific. Categorical and continuous data were compared
186
by the Chi-square and Mann-Whitney U tests, respectively. Survival analyses were done by the KaplanMeier method. Comparison of survival rates was calculated by the Log-rank test. Statistical Packages for
the Social Sciences v17.0 (SPSS Inc., Chicago, IL)
software was used for statistical analyses.
RESULTS
Ninety MM patients (54 male, 36 female, median
age: 61 years, range: 31-86) fitting to the inclusion
criteria were found. There were 17 patients (19%)
with test results compatible with IOP. At least one serum iron test was abnormal in the majority of cases
(69/90, 77%). Other iron parameter abnormalities
were classified as PID (1/90, 1%), PIA (20/90, 22%),
IIDI 6/90, 7%), and nonspecific (25/90, 28%). Only 2
IOP patients had red blood cell transfusion histories,
1 and 2 units weeks before the admission.
Demographic data, serum iron test results and some
disease-related characteristics of IOP cases and other
patients are presented in Table 1. Demographic data
were similar in IOP cases and others. Median (25-75
percentiles) serum ferritin level was 639 (266-753)
pg/ml in the IOP patients. TIBC level was similar in
the IOP cases and others. The main reason of elevated
TS in the IOP cohort was higher serum iron levels
(Table 1).
IOP was not associated with nephrotic syndrome or
renal dysfunction (Table 1). Marrow dysplasia was
not reported in any patient with IOP. Unfortunately,
marrow conventional cytogenetic analyses were
available in only 4 IOP patients. Two had normal and
2 complex karyotypes. Both complex karyotypes involved chromosome 1 abnormalities.
Mean baseline hemoglobin concentrations were
lower in IOP males and females compared to the corresponding genders in the control group. But, this
difference was not statistically significant in males.
Although IOP females had significantly lower hemoglobin levels this result should be interpreted with
caution as only 6 females were present in the IOP
cohort. Improvement of hemoglobin concentrations
were observed in IOP patients who attained very
good partial response or better (≥ VGPR) on followup (4 females, 10.8 g/dl (9.7-11.8) and 4 males, 12.9
(10.7-15.5)). White blood cell and platelet counts
were similar in IOP patients and controls (data not
presented).
There was a close association between lambda light
chain type paraproteinemia and IOP (13/17 vs 26/73
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International Journal of Hematology and Oncology
Table 1. Some important characteristics of iron overload patients in comparison to others
Iron overload patients
Male (n= 11)
Other patients
Female
(n= 6)
Male
(n= 42)
P value
Female
(n= 31)
Demir*
(F: 37-145 μg/dl)
124 (108-225)
123 (102-142)
58 (41-68)
60 (35-79)
M: 59-158 μg/dl)
< .001 (F)
< .001 (M)
Hemoglobin (g/dl)
9.3 (7.7-11.3)
8 (6.9-9.1)
9.8 (8.7-11.3)
9.8 (8.6-11.1)
.01 (F)
0.38 (M)
TIBC*,**
(228-448 μg/dl)
240 (195-275)
233 (194-283)
0.97
Age*
59 (52-69)
64 (55-72)
0.44
Albumin*
3.8 (3.7-4.3)
3.5 (3.0-3.9)
0.01
Beta2-microglobulin*
10520 (4870-15400)
5753 (2862-8109)
0.01
ISS*** stage 2 or 3#15
51
0.03
Kappa light chain type
4
46
0.003
Lambda light chain type
13
26
Soft tissue plasmacytoma(s)
4
5
0.04
Nephrotic syndrome
5
15
0.35
Renal failure
6
21
0.60
*Median (25-75 percentile)
**TIBC: Total iron binding capacity
***International staging system
#15 and 68 IOL and other patients were evaluable for ISS staging.
lambda paraproteinemia in IOP cohort and others respectively, p= 0.003). Half of the MM patients (7/14)
with free lambda light chain paraproteinemia had
IOP.
Four out of 17 IOP patients had soft tissue plasmacytomas and this was significantly more frequent
than the other patients (5/73) (p= 0.04). IOP patients
had higher-risk disease. International staging system
(ISS) stage 2 or 3 disease was present in all 15 IOP
patients with available data, compared to 51 out of
68 other patients (p= 0.03). However, we could not
observe any difference regarding treatment response,
overall- and progression-free survivals between IOP
cases and others (data not presented). This could be
due to low patient numbers.
Post-treatment repeat serum iron tests were available
in 9 patients with IOP and 1 patient had also serum
iron tests (completely normal) 6 months before the
diagnosis. 4 patients with responses ≥ VGPR showed
complete improvement of the iron tests. Three cases
with partial myeloma responses showed various responses in the iron tests. One had complete and 2 had
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partial improvements (i.e. partial improvement in TS
and/or residual hyperferritinemia). Two patients with
stable to progressive disease under treatment showed
no improvement in the iron tests.
DISCUSSION
An elevated TS level in a patient without liver dysfunction is a sensitive biochemical indicator for IO
12-13
.Clinical algorithms for detection of IO usually
start with this test. In this study, we found that serum
iron tests compatible with iron overload are not infrequent in MM at diagnosis. These results are related
to disease activity of MM. IOP in MM has important clinical associations, such as lambda light chain
(especially free light chain) disease, high-risk disease
and probably extramedullary disease.
It could be argued that the increased TS in IOP patients
was due to diminished transferrin level (i.e. TIBC)
which is a negative acute phase protein. However,
increased TS is not compatible with acute phase response. Additionally, serum iron level was frequently
borderline high to increased in the IOP cohort which
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International Journal of Hematology and Oncology
is not compatible with an acute phase response, too.14
There are very few studies focusing on iron in MM.
Most investigations considered iron in the context of
the anemia or acute phase reaction of MM.15-17 On
the other hand, Song et al.4 studied the importance
of serum ferritin in 89 patients with newly diagnosed
MM. They observed that the overall survival in the
elevated serum ferritin group was shorter than that
in the normal serum ferritin group (p< 0.001) after
a median follow-up of 25 months. In their study, elevated ferritin was correlated with poor survival and
was an independent predictor of mortality in MM
(p= 0.002).4 They observed an association between
increased ferritin level and advanced ISS stage. However, they did not report on other serum iron tests,
possible mechanisms of elevated ferritin in MM patients and the association between serum iron parameters and type of myeloma. Those findings together
with our iron results in this study cast attention to specifically search iron dynamics of MM in prospective
controlled studies.
The iron status in MM may also be important for the
long-term treatment response of the disease. Proteasome inhibition with bortezomib is a classical approach for the management of MM. The inhibition
of proteasome functionality could affect cellular iron
homeostasis and iron is a potent inducer of reactive
oxygen species and cell death, unless safely stored in
ferritin.5 Campanella and coworkers5 explored the potential role of iron in bortezomib-resistance. They analyzed iron proteins, oxidative status and cell viability
in 7 multiple myeloma cell lines and in plasma cells
from 5 patients. In their in vitro study, the cells were
treated with increasing bortezomib concentrations
with or without iron supplementation. The authors
reduced ferritin levels via the molecular methods and
by drug induced iron starvation. They observed that
MM cell lines were characterized by distinct ferritin
levels, which directly correlate with bortezomib resistance.5 Furthermore, iron supplementation upon
bortezomib promoted proteins oxidation and cell
death and that iron toxicity inversely correlates with
basal ferritin levels. In their study, bortezomib prevented ferritin up-regulation in response to iron, thus
limiting the ability to buffer reactive oxygen species.
Accordingly, the authors suggested that the modulation of iron status is a strategy worth to be explored to
improve the efficacy of proteasome inhibition therapies im MM.5 In our present study, four patients with
responses ≥ VGPR showed complete improvement
188
of the iron tests. Three cases with partial myeloma
responses showed various responses in the iron tests.
One had complete and 2 had partial improvements.
Two patients with stable to progressive disease under
treatment showed no improvement in the iron tests.
Therefore, the long-term effects of current pharmacological myeloma therapies including bortezomib,
thalidomide, and lenalidomide on iron status shall be
prospectively searched.
Iron may also be important in the pathobiology of
plasma cell neoplastic disorders.6-11 Ouellette et al.9
invented that iron in the presence of histidine enhanced cleavage of human immunoglobulin gamma
(IgG) molecules containing a lambda light chain. Using molecular methods, they demonstrated that the
cleavage resulted in elevated levels of free light and
heavy chain fragments.9 Since iron has a significant
role in the cleavage of lambda light chain IgG molecules9, the close association between lambda light
chain type paraproteinemia (especially free light
chain) and IOP (13/17 in IOP cohort vs 26/73 lambda
paraproteinemia, p= 0.003) in our present study could
be important. Half of the MM patients (7/14) with
free lambda light chain paraproteinemia had IOP in
our patient cohort.
The searching of iron status may open new avenues
in the treatment of MM. For instance, targeting the
human transferrin receptor 1 (CD71) may be effective in the management of MM.6 Rodriguez and
coworkers10 have developed recombinant antibodies
targeting human transferrin receptor 1, inducing receptor degradation and are cytotoxic to certain malignant B-cells. They showed that the internalization
of transferrin receptor 1 bound to those antibodies
can lead to its sequestration and degradation, as well
as reduced transferrin uptake, and the induction of a
transcriptional response consistent with iron deprivation, which is mediated in part by downstream targets of p53.10 Daniel et al. found that the cytotoxic
effects of HXR9 can be enhanced by combining it
with the antibody-avidin fusion protein specific for
the human transferrin receptor 1 (CD71).7 Iron starvation induced by the fusion protein contributes to
the enhanced effect and involves, at least in part, the
induction of a caspase-independent pathway. In another in vitro study, Ciclopirox olamine (CPX) bound
intracellular iron, and inhibited the iron-dependent
enzyme ribonucleotide reductase at concentrations
associated with cell death in myeloma.8 The underlying mechanisms and clinicopathological associations
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Number: 3 Volume: 24 Year: 2014
International Journal of Hematology and Oncology
of IOP in MM should be further evaluated not only
for academical purposes but also better future management of the patients.
In conclusion, serum iron tests compatible with iron
overload is not infrequent in MM at diagnosis. These
results are related to disease activity. IOP in MM
has important clinical associations, such as lambda
light chain disease, high-risk disease and probably
extramedullary disease. The underlying mechanisms
and its clinical associations should be further evaluated. Iron studies may open new ways in the management of MM.
10. Rodriguez JA, Luria-Perez R, Lopez-Valdes HE, et al. Lethal
iron deprivation induced by non-neutralizing antibodies targeting transferrin receptor 1 in malignant B cells. Leuk Lymphoma 52: 2169-2178, 2011.
11. Suzuki E, Daniels TR, Helguera G, et al. Inhibition of NF-kappaB and Akt pathways by an antibody-avidin fusion protein
sensitizes malignant B-cells to cisplatin-induced apoptosis.
Int J oncol 36: 1299-3107, 2010.
12. Piperno A. Classification and diagnosis of iron overload. Haematologica 83: 447-455, 1998.
13. Buyukasik NS, Nadir I, Akin FE, et al. Serum iron parameters
in cirrhosis and chronic hepatitis: detailed description. Turk J
Gastroenterol 22: 606-611, 2011.
14. Wallach J (Ed). Interpretation of diagnostic tests. 8th edition.
Philadelphia, Lippincott Williams and Wilkins, 2007: 270-271.
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Correspondence
Dr. Eylem ELİAÇIK
Hacettepe Üniversitesi Tıp Fakültesi
Hematoloji Anabilim Dalı
Sıhhiye / ANKARA
Tel: (+90.312) 305 15 43
mail: [email protected]
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